Requirements of NK Cells and Proinflammatory Cytokines in T Cell-Dependent Neonatal Autoimmune Ovarian Disease Triggered by Immune Complex

Abstract

A model of neonatal autoimmune disease has been described recently in which an epitope-specific autoantibody to murine zona pellucida 3 induces severe ovarian disease in neonatal, but not adult, mice (neonatal AOD). The autoantibody forms immune complex with endogenous ovarian zona pellucida 3, and a pathogenic CD4+ T cell response is triggered. The basis for the predominant neonatal susceptibility has not been clarified. In this study innate immunity, including neonatal NK cells, in neonatal AOD was investigated. Neonatal spleen contained readily detectable NK1.1+TCRVβ−, but not NK1.1+TCRVβ+, cells. Ab depletion of NK1.1+TCRVβ− cells inhibited neonatal AOD development. Moreover, in adoptive transfer of neonatal AOD, recipient disease was ameliorated when either donor or recipient NK cells were depleted. Thus, NK cells operate in both induction and effector phases of the disease. IFN-γ was produced by neonatal NK cells in vivo, and it may be important in neonatal AOD. Indeed, ovaries with neonatal AOD expressed high levels of IFN-γ and TNF-α which correlated with disease severity, and the disease was inhibited by IFN-γ or TNF-α Ab. Importantly, disease was enhanced by recombinant IFN-γ, and treatment of T cell donors with IFN-γ Ab also significantly reduced adoptive transfer of neonatal AOD. Finally, neonatal AOD was ameliorated in mice deficient in FcγRIII and was enhanced in FcγRIIB-deficient mice. We conclude that neonatal NK cells promote pathogenic T cell response at multiple stages during neonatal autoimmune disease pathogenesis. Also operative in neonatal AOD are other mediators of the innate system, including proinflammatory cytokines and FcγRIII signaling.

The role of Natural Killer cells in the pathogenesis of rheumatoid arthritis: Major contributors or essential homeostatic modulators?

“…However, whether NK cells promote or protect against autoimmunity remains unclear with evidence from cell depletion studies suggesting that NK cells play a role in both promoting and limiting autoimmunity in different disease models and different stages of autoimmune responses. A protective role for NK cells has been reported in animal models of diabetes [60], colitis [61] and experimental autoimmune encephalomyelitis [62,63], while in contrast, NK cells have been shown to promote autoimmunity in models of neonatal autoimmune ovarian disease [64] and experimental autoimmune myasthenia gravis [65]. Recent reports have also outlined conflicting results on the effect of NK cell depletion in animal models of arthritis [66,67].…”

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

“…Recent studies of both autoimmune disease (52) and allogeneic IUHCT (53) rism (<1.8%) despite the presence of T cell tolerance. Our findings of transfer of maternal alloantibodies would suggest that a possible mechanism for this observation is activation of donor MHC class I-specific NK cells by maternal alloantibody via an ADCC mechanism in a milieu of low frequencies of donor cells.…”

The Unique Neonatal NK Cells: A Critical Component Required for Neonatal Autoimmune Disease Induction by Maternal Autoantibody

“…Complement C3b and C5b were undetectable in ovaries of mice with nAOD. However, studies with blocking antibodies and gene KO mice indicated that nAOD is dependent on FcγRIII expression (44, 58). In fact, we found that TD-nAOD pathogenesis requires both FcγRIII-dependent ADCC and a de novo T cell response.…”

“…In fact, we found that TD-nAOD pathogenesis requires both FcγRIII-dependent ADCC and a de novo T cell response. First, the neonatal NK cell must express FcγRIII to support nAOD (58). Second, the critical CD4 + T cells are required in TD-nAOD because (1) T cell depletion prevents nAOD, (2) CD4 + T cells from mice with nAOD transfer ovarian disease to naïve pups (44).…”